A trial for producing a gel by using nucleic acid, in particular, DNA has been reported (Non-patent Document 1). In the method disclosed in Non-patent Document 1, the ends of a DNA monomer are subjected to covalent linkage by using a DNA ligase. More specifically, Non-patent Document 1 reports that DNA chains each having a complementary sequence at the ends are synthesized; X-type DNA, Y-type DNA, and T-type DNA are produced by using a T4 ligase; and a hydrogel is produced by using such DNAs. However, since the gel produced by using the DNA disclosed in Non-patent Document 1 includes a remaining enzyme (DNA ligase) which is used for gelation, there have been problems in terms of safety and antigenicity.
Furthermore, the method disclosed in Non-patent Document 1 needs an enzyme reaction for gelation, and thus when a gel is administered to a living body, the gel is produced outside the living body in advance, and needs to be administered in its original form. This is a large limit to administration. Furthermore, the gelation reaction disclosed in Cited Document 1 is reaction using an enzyme, and thus in order to enclose a relatively large substance into a gel, it is necessary to add a substance to be enclosed at the time of gelation, that is, a ligation reaction. However, this has a high risk for damaging a function of the substance to be enclosed. Furthermore, with the gel prepared by using a ligase, sufficiently high viscoelasticity can not be obtained.
In addition to this, a large number of trials for formation of a hydrogel including DNA as a constituent element have been carried out. There have been many reports of formation using chemical cross-linking, formation depending upon heat and pH and the like (Non-patent Documents 2, 3 and Patent Document 1).
For example, Non-patent Document 2 reports that DNA extracted from salmon testis is chemically cross-linked (with the use of ethylene glycol diglycidyl ether), 1 M NaOH and TEMED are then added thereto, and the mixture is heated for about two hours (50° C.) to obtain a gel. In such a method, however, an organic compound is used which is concerned about safety to a living body in addition to nucleic acid, and therefore the safety in administration of the gel to a living body is concerned. Furthermore, the gelation needs heating, and therefore a substance that is easily denatured cannot be contained.
Furthermore, Non-patent Document 3 relates to production of pH-dependent Y-type DNA. The method utilizes a change of a state of a DNA molecule dependent upon pH change. This method permits gelation by adding HCl into a DNA solution so as to be acidic. Substances that have once been gelled can be returned to be a state of solution by adding NaOH. However, in order to maintain a gel state, the environment is required to be kept to be acidic, thus making the gel to be unstable with respect to the surrounding environment.
Patent Document 1 discloses a method for providing a synthesis hydrogel, which does not include a chemical reaction or a polymerization reaction, and which can simply and rapidly produce a hydrogel having sufficient strength around the body temperature (37° C.) in a physiological condition. The gel obtained by the method is a hydrogel obtained by mixing a water-soluble polymer such as polysaccharide and nucleic acid with each other, and permits temperature-dependent gel-sol transition. However, the gel contains a large amount of polysaccharide, and therefore it cannot be said that the gel is a hydrogel composed of nucleic acid.
Meanwhile, various hydrogel formulations have been developed utilizing gelatin, a synthesized polymer, or the like. Also in the case of the gels prepared therefrom, the gelation is carried out before administration, and systems to be gelled after administration are few. Also, injectable gels are reported, but they are gels having a submicron to micron size capable of passing through an injector needle. Therefore, in a case of administration by injection or the like, minute gels are used and, in such a case, gel properties such as sustained release properties are largely damaged.
Furthermore, hydrogels using sol-gel transition by temperatures have been reported in plural documents (for example, Patent Document 2). However, compounds to be used partially utilize chemical modification, and therefore the gels are not gels composed of pure natural materials such as nucleic acid.
It should be noted that many trials using CpG DNA as an adjuvant have been made. Reports of enhancement in activating ability by cholesterol modification or phosphorothioation have been made. However, in such cases, even when the adjuvant (CpG DNA) and an antigen are administrated simultaneously, there is a concern that behaviors thereof in a living body may be carried out separately. Furthermore, in the case of phosphorothioate-type DNA, there is a problem that tissue disorder may occur by high protein binding properties.